Sepsis and Septic shock

Surviving Sepsis Guidelines:  In their own words of wisdon – " The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when presented with a patient’s unique set of clinical variables. These guidelines are intended to be best practice and not created to represent standard of care".
The clinician may push back from use of recommendations for fear that evidence-based guidelines lead to “cookie cutter” medicine and reflexive behaviors that deemphasize the “art” of medicine.The recommendations are intended for a “typical” septic patient. Patients still benefit from the art of medicine, which includes interpretation of data and individualization of treatment. The recommendations provide much needed general treatment guidance to the bedside decision maker who is busy, pressured to see more patients in less time, and who will use a distillation of the current literature into a coherent set of recommendations suitable for the large majority of septic patients who are “typical”.
Sepsis is defined as presence of infection, which can be proven or suspected, and 2 or more of the following criteria: 
  • Temp  > 38.3 degrees C ( 101 F) or less than < 36 degrees C (<96.8 degrees F) 
  • Tachypnea, RR>20 or PaCO2 <32 
  • Heart rate > 90 
  • WBC > 12,000 or < 4,000 or with >10% “bands” (immature forms) 
  • Hypotension (systolic blood pressure < 90 mm Hg or fallen by >40 from baseline, mean arterial pressure < 70 mm Hg) 
  • Lactate > 1 mmol/L 
  • Hyperglycemia (>140 mg/dL) in someone without diabetes 
  • Elevated CRP or Procalcitonin , 2 times normal 
  • Arterial hypoxemia (paO2 / FiO2 < 300) 
  • Significant edema or positive fluid balance (>20 mL/kg over 24 hours) 
  • Oliguria, with urine output (<0.5 ml/kg/hr for at least 2 hours despite fluid resuscitation   
  • Creatinine increase > 0.5 mg/dL 
  • INR > 1.5 or aPTT > 60 seconds 
  • Platelet count < 100,000 
  • High bilirubin (total bilirubin > 4 mg/dL 
  • Absent bowel sounds (ileus)  
  • Change in mental status 
  • Decreased capillary refill of nail beds or skin 
  • Mottled skin 
Severe sepsis is sepsis with impaired blood flow to body tissues (hypoperfusion) or detectable organ dysfunction. Severe sepsis may occur with or without sepsis-induced hypotension. 
Septic shock is severe sepsis with sepsis-induced hypotension [SBP < 90 mm Hg or a drop of > 40 mm Hg from baseline) or MAP < 70 mm Hg] that persists after adequate fluid resuscitation.  
The major pathophysiologic changes in patients with severe sepsis and septic shock include vasoplegic shock (distributive shock), myocardial depression, altered
microvascular flow, and a diffuse endothelial injury. The widespread endothelial injury results in a microvascular leak, with tissue and organ edema, hypotension, and shock. Increased endothelial permeability is caused by shedding of the endothelial glycocalyx and the development of gaps between endothelial cells (paracellular
leak). Vasoplegic shock due to the failure of the vascular smooth muscle to constrict, results in arterial and venodilatation. Venodilatation decreases venous return and compounds the intravascular volume deficit caused by the vascular leak.
Chest. 2014 Jun;145(6):1407-18,  N Engl J Med 2001; 345:588-595
Early Goal-Directed Therapy for Severe Sepsis/Septic Shock ( as mentioned in old sepsis guidelines)
The goals during the first 6 hours of resuscitation should be (Grade 1C): 
  1. Mean arterial pressure (MAP) ≥ 65 mm Hg
  2. Central venous pressure (CVP) 8-12 mm Hg (12-15 mm Hg in patients receiving mechanical ventilation or with known preexisting decreased ventricular compliance). However, CVP has been proven to be unreliable indicator of fluid status and can't be used soley to drive fluid resuscitation. Chest. 2008 Jul;134(1):172-8 , Crit Care Med. 2013 Jul;41(7):1774-81
  3. Central venous oxygen saturation (from the superior vena cava) SCVO2 ≥ 70%, or mixed venous oxygen saturation (from a pulmonary artery catheter) ≥ 65%. Patients who are septic may have a normal or increased Scvo2 caused by reduced oxygen extraction. Infact, higher ScVO2 may indicate very sick tissues and may lead to worse mortality rates. Ann Emerg Med. 2010 Jan;55(1):40-46.e1 ( Lactate clearance of 25% has been found to be equivalent to ScVo2 measurements and hence, it is falling out of favour) Crit Care Med. 2004 Aug;32(8):1637-42
  4. Urine output ≥ 0.5 mL/kg/hr 
  5. Lactate clearance: An elevated lactate concentration is a consequence of increased aerobic glycolysis as part of the stress response and that titrating therapy to the rate of decline in lactate concentration is a potentially harmful endeavour. Furthermore, an increased lactate concentration may be an important adaptive survival response during critical illness. OA Critical Care, 1 (1) (2013), p. 3
  • In a study reviewing the outcomes of patients enrolled in the Surviving Sepsis Campaign database, the attainment of a CVP of >8 mm Hg and Scvo2 of > 70% did not influence survival in patients with septic shock. Emerg Med J. 2011 Jan;28(1):3-4
  • Crystalloid is recommended for initial fluid resuscitation for severe sepsis and septic shock. A minimum of 30 ml/kg of crystalloids be given in the first 3 hours and additional fluids can be given as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables.  
  • Surviving sepsis guidelines recommend to consider albumin fluid resuscitation if large volumes of crystalloid are required to maintain intravascular volume. ( ?If large volumes of crystalloid are needed to maintain intravascular volume, patient may actually not be fluid responsive and actually need vasopressors instead of more fluids or albumin). Metaanalysis of all studies that compared albumin vs crystalloids showed some mortality benefit with albumin in septic shock, especially when given less than 6 hours from identification of septic shock. 
  • All isotonic solutions get distributed throughout the extracellular space but not intracellular space. So, for each litre of NS infused, only 1/4th stays intravascularly and 3/4th goes into interstitial component. 
  • Vasopressors should be begun within 6 hours for patients with hypotension despite aggressive initial fluid resuscitation (i.e., septic shock), to maintain a mean arterial pressure ≥ 65 mm Hg. Recent data indicate that vasopressors started even within the first hour while fluid resuscitation is being carried out tend to have better outcomes. The goal is to never allow drop in MAP thereby preventing end organ damage in the early phases of resuscitation. Crit Care. 2014 Oct 3;18(5):532Crit Care. 2014; 18(6): 691 
  •  The goal of attaining a mean arterial pressure (MAP) of ≥ 65 mm Hg for patients receiving vasopressors for septic shock is based on very limited evidence. Accordingly, the Surviving Sepsis Guidelines advise that “the optimal MAP should be individualized” during treatment of septic shock — perhaps higher than 65 mm Hg in a patient with hypertension and known atherosclerosis; perhaps lower than 65 mm Hg in a young healthy patient with a baseline normal blood pressure — and that other markers of perfusion such as serum lactate, skin appearance and temperature, urine output, and mental status should supplement the use of mean arterial pressure in all patients. 
  • Transfusion of packed red blood cells to a hematocrit of 30% and/or dobutamine infusion in patients with low ScVO2, despite volume resuscitation,  have not been proven to be beneficial and use of them is strongly discouraged. 
  • Lactic acidosis in sepsis: SSC recommends serial measurent of lactate until normalization of lactate level. They also recommend that in patients whose blood pressure has been restored to normal after fluid resuscitation, but still have lactate elevations ≥ 4 mmol/L , goal-directed therapy with serial measurements of CVP, ScVO2 and lactate should continue until these parameters improve. The rationale is that an elevated lactate is a consequence of tissue hypoxia and inadequate oxygen delivery. However, multiple studies have demonstrated that the increased blood lactate concentration in sepsis is not caused by tissue hypoxia but is rather produced aerobically as part of the metabolic stress response. A high lactate concentration should be interpreted as a marker of disease, portending a bad outcome. The presence of hyperlactataemia in resuscitated septic patients should not be taken as proof of oxygen debt needing increases in systemic or regional oxygen transport to supranormal values. Lactate, instead of being regarded only as a marker of hypoxia, might be an important metabolic signal. Lancet. 1999 Aug 7;354(9177):505-8 , Lancet. 2005 Mar 5-11;365(9462):871-5 , Lancet Diabetes Endocrinol. 2014 Apr;2(4):339-47J Intensive Care. 2015; 3: 39.
  1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobials.  At least 2 sets of blood cultures (Both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted. Sterilization of cultures can occur within minutes to hours after first dose of antibiotics. All cultures can be drawn at the same time. Blood culture yield has not been shown to be improved with sequential draws or timing to temperature spikes. 
  2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available, and invasive candidiasis is in differential diagnosis of cause of infection.   
  3. Imaging studies performed promptly to confirm a potential source of infection (UG).  
  4. If blood cultures from vascular device are positive earlier then peripheral cultures, vascular device is likely the source of infection. 
  5. The volume of blood drawn with each culture tube should be ≥ 10 mL 
Initial Antibiotic / Antimicrobial Therapy in Severe Sepsis/Septic Shock: 
  • For severe sepsis or septic shock, give antimicrobials “within the first hour” after severe sepsis or septic shock is recognized. Each hour delay in administering antibiotics is associated with increased mortality.  Crit Care Med. 2006 Jun;34(6):1589-96.
  • SSC recommend double gram negative coverage for the intial management of septic shock but not for sepsis without shock. 
  • Antimicrobials should be chosen that cover all the likely causative pathogens — nearly always including bacteria, but sometimes also fungi and/or viruses. 
  • Antimicrobials should be selected that are expected to penetrate into the presumed infected tissues. 
  • For patients at risk for fungal infection as a source for severe sepsis, checking one of the newer assays for invasive candidiasis such as 1,3-beta-D-glucan, mannan, or anti-mannan ELISA antibody testing 
  • Review the antibiotic / antimicrobial regimen daily, and de-escalate therapy whenever appropriate. Strength: Grade 1B (strong recommendation with moderate-quality evidence). 
  • Consider using Procalcitonin to help gain confidence in stopping empiric antibiotics in patients who appeared to have severe sepsis or septic shock at first, but now have a lower suspicion for infection.  Strength: Grade 2C (weak recommendation with low-quality evidence). Viral infections tend to increase the cytokine interferon-gamma, which inhibits procalcitonin release–resulting in lower levels of procalcitonin during viral infection.  
  • Use combination therapy (multiple drugs active against the same organisms, through different mechanisms of action) when appropriate, but for only a limited time (3-5 days). If positive cultures and sensitivity data are available sooner than 3-5 days, narrow antibiotic use as soon as data is available.  
  • Combination therapy is recommended for septic shock or severe sepsis with Neutropenia, MDR bacteria like Pseudomonas, Acinetobacter, et al. or sepsis with respiratory failure.  
  • Use an extended-spectrum beta-lactam and either a fluoroquinolone or aminoglycoside in Pseudomonas aeruginosa bacteremia causing septic shock and respiratory failure  
  • Combine a beta-lactam and a macrolide in Streptococcus pneumoniae with bacteremia and septic shock. 
  • Treat most infections in people with severe sepsis / septic shock for 7-10 days total. Longer treatment might be appropriate for patients who are responding slowly, have abscesses, empyema, or other infectious foci not amenable to drainage, have Staphylococcus aureus bacteremia, have unusual infections (e.g., fungal or viral) or have immune deficiencies (e.g., neutropenia).  Shorter courses are appropriate in some patients, particularly those with rapid clinical resolution following effective source control of intra-abdominal or urinary sepsis and those with anatomically uncomplicated pyelonephritis. 
Source Control  
1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C).  
2. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established.  
IV fluids:
Pathophysiologically, sepsis is characterized by vasoplegia with loss of arterial tone, venodilation with sequestration of blood in the unstressed blood compartment and changes in ventricular function with reduced compliance and reduced preload responsiveness. Sepsis is not a volume-depleted state and recent evidence demonstrates that most septic patients are poorly responsive to fluids. Furthermore, almost all of the administered fluid is sequestered in the tissues, resulting in severe oedema in vital organs and, thereby, increasing the risk of organ dysfunction. Newer data suggest that a physiologic, haemodynamically guided conservative approach to fluid therapy in patients with sepsis would be prudent and would likely reduce the morbidity and improve the outcome of this disease. Br J Anaesth. 2016 Mar;116(3):339-49
Beyond the early administration of antibiotics, aggressive “supportive measures” may be harmful and the “less is more” paradigm appears applicable for the management of patients with severe sepsis. In these highly vulnerable patients, more intensive treatment may promote the chance of unwanted adverse effects and, hence, iatrogenic injury. In a latest prospective study in african children, mortality was higher in people who are fluid resuscitated with iv fluids or albumin compared to those who are not fluid resuscitated at all. The mortality was even higher in people who are resuscitated with both fluids and albumin. FEAST Trial
Current teaching suggests that aggressive fluid resuscitation is the best initial approach for the cardiovascular instability of sepsis. Consequently, large volumes of fluid (5-10 L) are often infused in the early stages of sepsis. There is, however, no human data that substantial (> 30 mL/kg) fluid resuscitation reliably improves BP or end-organ perfusion. There is also no controlled data exist that increases in cardiac output due to volume expansion are beneficial or even reliably achieved. Crit Care. 2012 Jan 25;16(1):302 , Crit Care. 2011;15(3):164 , Chest. 1999 Nov;116(5):1354-9.
Increased cardiac filling pressures consequent to large-volume resuscitation increase the release of natriuretic peptides. Natriuretic peptides cleave membrane-bound proteoglycans and glycoproteins off the endothelial glycocalyx. The endothelial glycocalyx plays a major role in regulating endothelial permeability, and damage to the glycocalyx plays a major role in increasing tissue edema. Because of the endothelial injury, capillary leak, and increased hydrostatic pressures, < 5% of infused crystalloid remains intravascular within 3 h after infusion, resulting in an increase in EVLW and further tissue edema. 
Multiple clinical studies have demonstrated an independent association between an increasingly positive fluid balance and increased mortality in patient with sepsis. FEAST Study, Crit Care Med. 2011 Feb;39(2):259-65Crit Care. 2013 Oct 20;17(5):R246Respir Med. 2008 Jul;102(7):956-61 , Chest. 2000 Jun;117(6):1749-54
Even though surviving sepsis guidelines recommend 30cc/kg fluid bolus for everyone on admission to ED, its important to still look at the individual patient factors. If patient is clearly volume overloaded ( CHF, ESRD, Cirrhosis of liver with ascites), its imperative to use clinical judgement and not bombard them with iv fluids, just because guidelines said so. In VASST study, optimal survival occurred with a positive fluid balance of approximately 3 L at 12 h. In ARISE study, 2.2 ± 1.9 L of fluid were given in the first 6 h. The hospital mortality was 23% in the ARISE study compared with 30% in the intervention arm of the EGDT study.
In volume overloaded patients, the cardiac muscle fibre is already overstretched ( think of frank-starling curve). If we add more volume, we will make the muscle fibre stretch even more with resultant decrease in contractility and thereby a decrease in cardiac output. Infact, in volume overloaded patients, giving careful diuretics when appropriate, may bring the muscle fibre to optimal length and may improve contractility with improved cardiac output. Recent studies also showed that early use of vasopressors rather than waiting for MAP to be stabilized with iv fluids results in better outcomes.  













If the primary goal of IV fluids is to restore the volume status, only give just enough fluids to restore euvolemia. 
Diastolic pressure is a surrogate marker of vascular tone. If vasodilatory shock, diastolic pressure is low and in hypovolemic shock, diastolic pressure will be normal. It might give a sense of how much shock is due to vasodilation and how much due to volume depletion. 
Also, we see quite often that patient becomes septic while admitted on the floor and they are given 30cc/kg fluid bolus for hypotension and possibly, even more. Those patients don't go from euvolemia to hypovolemia with sepsis alone and all they may need is vasopressors alone, instead of iv fluids. ( We can't treat vasodilatory shock as hypovolemic shock). Also, its very common in practice to give IV fluids as infusions. Remember, use iv fluids only if you think patient is hypovolemic. If patient is infact hypovolemic, replace all the volume in a much expedited fashion, preferably as boluses. ( Fluid bolus by definition should be pressure bagged and 1 litre should be given within 8 mins, not 999ml/hr). By giving boluses, we are rapidly restoring intravascular volume and can watch the dynamic variables to see if the patient is fluid responsive. 
Sepsis induced cardiomyopathy: Incidence of biventricular failure from sepsis is as high as 60%. Crit Care Med. 2008 Jun;36(6):1701-6. Bedside ECHO might help in evaluating the cardiac function and can help in the optimal dose of iv fluids. Dobutamine or milrinone can be added if there is any evidence of systolic dysfunction. One of the most common reasons for worsening lactate inspite of adequate MAP is sepsis induced cardiomyopathy. If we fail to diagnose it, quite often clinicians tend to give more iv fluids trying to wash out lactate and that could be lethal. 

Vasopressors for Septic Shock 

Optimal time to start a vasopressor agent in patients with sepsis has not been well studied. After receiving 20 to 30 mL/kg of crystalloid, it seems unlikely that additional fluid boluses will result in a sustained increase in mean arterial pressure, even though transient rise in blood pressure could be achieved. Restoration of blood pressure with vasopressors results is recruitment of microvasculature and better tissue oxygenation. 
Norepinephrine (Levophed), epinephrine, vasopressin, phenylephrine, and dopamine are the most commonly used vasopressors for septic shock. 
  • Vasopressors should be begun initially to target a MAP of 65 mm Hg. 
  • Norepinephrine (Levophed) should be provided as the first-line vasopressor and titrate up to 35-90 µg/min. Norepinephrine increases mean arterial pressure primarily through vasoconstriction ( both venous and arterial ), with little effect on heart rate, stroke volume, and cardiac output.  
  • Vasopressin at 0.03 units/minute is appropriate to use with norephinephrine, either to improve perfusion (increase MAP) or to reduce the required dose of norepinephrine. Vasopressin is not recommended for use as a single vasopressor for septic shock. Vasopressin doses higher than 0.03 – 0.04 units/min are recommended to be reserved only when septic shock is refractory to standard doses of multiple vasopressors (ungraded recommendation). 
  • Epinephrine is considered the next-line agent for septic shock after norepinephrine. When norepinephrine is insufficient to maintain MAP 65 mm Hg, epinephrine at the dose of 20-50 mcg/min should be added to or substituted for norepinephrine. Epinephrine may increase lactate concentrations by stimulating skeletal muscles aerobic metabolism, thereby interfering with the use of lactate as a marker of perfusion during treatment of septic shock. 
  • Dopamine is suggested to not be used as an alternative to norepinephrine in septic shock, except in highly selected patients such as those with inappropriately low heart rates (absolute or relative bradycardia) who are at low risk for tachyarrhythmias. Dopamine is recommended to not be used in low doses in a so-called renal-protective strategy (Grade 1A). 
  • Phenylephrine at a dose of 200-300 mcg/min  can be added when septic shock persists despite the use of 2 or more inotropic/vasopressor agents along with low-dose vasopressin; or cardiac output is known to be high, or norepinephrine is considered to have already caused serious arrhythmias. 
  • An arterial catheter for hemodynamic monitoring should be placed as soon as practical, if resources are available, for all patients requiring vasopressors (ungraded recommendation). 
  • Dobutamine may be tried for patients in septic shock who have low cardiac output with high filling pressures while on vasopressors, or who have persistent evidence of hypoperfusion after attaining an adequate mean arterial pressure and intravascular volume (with or without vasopressors) (Grade 1C). 
  • A dobutamine infusion up to 20 mcg/kg/min can be added to any vasopressor(s) in use. Dobutamine is also an appropriate first-line agent in patients with severe sepsis and low cardiac output, with a preserved mean arterial pressure (i.e., who are not in septic shock) (Grade 1C). 
  • Dobutamine is recommended not to be used to deliberately raise cardiac output to higher than normal levels in an attempt to improve perfusion (Grade 1B). 
  • In patients with vasopressor-refractory septic shock, IV hydrocortisone in a continuous infusion totaling 200 mg/24 hrs is recommended. No need for cortisol testing or ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. No benefit of continuous vs. bolus infusions has been demonstrated (continuous produces less hyperglycemia, but more of a rebound effect after discontinuation). 
  • Random cortisol levels may still be useful for absolute adrenal insufficiency; however, for septic shock patients who suffer from relative adrenal insufficiency (no adequate stress response), random cortisol levels have not been demonstrated to be useful.  
  • Consider steroids in high risk patients (multi-organ failure) acknowledging that septic shock may reverse more quickly but will not change mortality ( CORTICUS Trial 
Transfusion of blood products in Sepsis and Septic Shock 
The Surviving Sepsis Guidelines advocate restricting red blood cell transfusion in adults with severe sepsis/septic shock until hemoglobin falls below 7.0 g/dL, and not transfusing above 9.0 g/dL, if ischemic heart disease, severe hypoxemia, or active bleeding are not present.  
For patients with severe sepsis and septic shock, the Surviving Sepsis Guidelines suggest transfusing platelets prophylactically only when platelets fall to 10,000 / mm3, assuming no bleeding is present. In patients considered at significant risk for bleeding, a threshold of 20,000 / mm3 is suggested, and for those with active bleeding or who are undergoing surgery or invasive procedures, transfusing platelets to 50,000 mm3 is suggested.  
Mechanical ventilation in Sepsis: 
Low tidal volumes and plateau pressures should not just be used in people with full-blown ARDS, but virtually everyone with sepsis, because observational trials suggest a decreased risk for ARDS when lower tidal volumes are used (Ungraded). 
Glucose Control  
1. A protocolized approach should target an upper blood glucose ≤180 mg/dL rather than an upper target blood glucose ≤ 110 mg/dL.  
2. Blood glucose values are monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter.   
3. Glucose levels obtained with point-of-care testing of capillary blood are interpreted with caution; such measurements may not accurately estimate arterial blood or plasma glucose values.  
Deep Vein Thrombosis Prophylaxis  
  • Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE). This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, grade 2C versus three times daily UFH).  
  • Patients with severe sepsis are treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible.  

 Stress Ulcer Prophylaxis

  • Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor is given to patients with severe sepsis/septic shock who have bleeding risk factors (grade 1B). ​
  • When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA  
1. Administer oral or enteral feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C).  
2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day), advancing only as tolerated (grade 2B).   
3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B).  
Unresolved Sepsis: 
Could be due to non-infectious cause like drug fever, source still present like infected lines, MDR pathogens, inappropriate antibiotics, unusual sources like meningitis, sinusitis, cavernous sinus thrombosis, DVT, thrombophlebitis, C.Diff, Prosthetic devices or tumor fever. 
Renal Replacement therapies: 
Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. However, all those studies are done on patients who are hemodynamically stable. 
Steroids in septic shock:
The use of low-dose corticosteroids in patients with severe sepsis remains controversial. corticosteroids may have beneficial effects in sepsis, including increasing adrenergic responsiveness and preserving the endothelial glycocalyx. Steroids are likely to be beneficial early in the course of the disease, especially within 6  hours after onset of septic shock. Crit Care. 2012 Jan 7;16(1):R3JAMA. 2009 Jun 10;301(22):2362-75 . The ongoing ADRENAL study might provide some answers that we need to know. 
Bicarbonate for Lactic acidosis: 
Do not use sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH >7.15 (grade 2B). 
Vitamin C in septic shock:
Vitamin C has strong immunomodulating and antioxidant activity. As such, vitamin C is promoted as adjuvant therapy in conditions characterized by excessive oxidative stress or crippled immunity such as ischemia-reperfusion disorders, trauma, and various inflammatory disease processes. For example, in patients with septic shock and dialysis ,vitamin C is substantially cleared by dialysis and at least 50% of ascorbate may be lost during CRRT.
Evidence is emerging that parenteral administration of high-dose vitamin C can prevent or restore reactive oxygen radical-induced microcirculatory flow impairment, prevent or restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier and augment antibacterial defense. Critical Care 2014, 18:460J Thorac Dis. 2016 Sep; 8(9): E993–E995,  J Res Pharm Pract. 2016 Apr-Jun;5(2):94-100J Transl Med. 2014 Jan 31;12:32 , Crit Care. 2015 Nov 27;19:418
In a recent trial by Dr.Marik, early use of intravenous vitamin C, together with corticosteroids and thiamine proved to be effective in preventing organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock. The hospital mortality was 8.5% in the treatment group compared to 40.4% in the control group (p < 0.001). Mean duration of vasopressors was 18.3 ± 9.8 hours with vitamin C protocol vs. 54.9 ± 28.4 hours in the control group (p<0.001). Chest. 2016 Dec 6. pii: S0012-3692(16)62564-3.
Cardiac output monitors in ICU: Recently, number of cardiac output monitors came into the market like FLOTRAC, LIDCO, PICCO and NICO monitors. they all are pulse contour based. The problem with these devices are that people fail to understand when to use these machines. They are useful when there is ambiguity of giving fluids. In my opinion, these monitors should not be used when the patient is clearly fluid overloaded or already in significant positive fluid balance. Regardless of what these machines say, if a patient is already in significant positive fluid balance ( >5 liters), there is no indication for extra fluids. An excellent review by Dr.Marik on cardiac output monitors can be found here.
Clinical Trials: 
  1. Does CVP predict fluid responsiveness ( by Paul Marik) : There is a very poor relationship between CVP and blood volume as well as the inability of CVP/ΔCVP to predict the hemodynamic response to a fluid challenge. CVP should not be used to make clinical decisions regarding fluid management. Chest. 2008;134(1):172-178,   Crit Care Med. 2013 Jul;41(7):1774-81

  2. Dopamine vs. Levophed (SOAP II Trial): Although there was no significant difference in mortality between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. Dopamine was also associated with more arrhythmias. A sub group analysis revealed that there was increased mortality with dopamine in cardiogenic shock but no difference in septic or hypovolemic shock. We would expect to maintain higher cardiac output with dopamine and lesser mortality but possibly more arrhythmias resulted in increased mortality in cardiogenic shock. N Engl J Med 2010; 362:779-789 
  3. Dopamine vs. LevophedIn patients with septic shock, dopamine administration is associated with greater mortality and a higher incidence of arrhythmic events compared to norepinephrine administration. Crit Care Med. 2012 Mar;40(3):725-30 
  4. Albumin vs. Saline (SAFE Trial)In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days, which includes ICU days, vent days, or days on renal replacement therapy or 28 day mortality rates. N Engl J Med 2004; 350:2247-2256 
  5. Albumin in Severe sepsis (ALBIOS study): In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days, even though it improved hemodynamic variables. N Engl J Med. 2014 Mar 18 
  6. Early goal directed therapy (Rivers study):  Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy.  
Of note, at baseline, EGDT group have lower CVP, lower MAP, lower SVO2, higher lactate, higher APACHE II score, higher SAPS II score, and higher MODS. At 7-72 hour mark, the patients assigned to early goal directed therapy had significantly higher central venous oxygen saturation, a lower lactate, a lower base deficit, and a higher pH than the patients assigned to standard therapy.  
The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 %. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started. N Engl J Med 2001; 345:1368-1377 
  1. Protocol based care in septic shock (PROCESS trial): Protocol-based resuscitation (EGDT) of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. There was no difference in 60 day mortality in protocol based EGDT, protocol based standard care or physician led standard care. The need for RRT was higher in protocol based standard care 
 The key aspects in protocol for standard therapy are use of peripheral 18G IV’s, fluid bolus of 2 litres within 1 hour with first 500-1000ml in 20 mins, no dobutamine, use of vasopressors if SBP<100 or shock index>0.8 ( Heart rate/SBP) after being fluid replete and no need for SVO2.  It also strongly discouraged CVP and SVO2 measurements. Of note, vasopressors were started immediately once patient is fluid replete.  N Engl J Med. 2014 Mar 18
  1. Etomidate in sepsis: Etomidate was associated with increased mortality among septic patients, possibly due to adrenal suppression, even though there was no direct evidence. Crit Care Med 2012; vol 40(11):2945-53
  2.  ARISE Trial( EGDT vs Usual Care):  In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days ( 18.6% EGDT vs. 18.8% usual care group ). There was also no difference in Hospital & ICU LOS. N Engl J Med 2014; 370:1683-1693

Key pointers: 
  • Compared with Process trial, the vasopressors requirements in both groups at baseline are the same. 
  • Volume of fluid administered during the first 6 hours was EGDT 1964+/-1415 vs. Usual-care group 1713+/-1401ml . ​
  • Between 6 and 72 hours, the proportion of patients receiving vasopressor infusions was higher in the EGDT group than in the usual-care group (58.8% vs. 51.5%) 
  • Around 33% of patients got steroids in both groups. 
  • Mortality rate for APCHE II scores >25 is 45% 
  • Blood cultures were positive in 38% of patients. 
  • IV fluids given were 2.5 litres before randomization, 1.7 to 1.9 litres in first 6 hours and then 4.2 litres between 6-72 hours. 
  • Vasopressor use was significantly less in usual care group in both first 6 hours as well as 6-72 hrs.  
  • Average CVP was 11 from 0-72 hours 
  • Average MAP was 75 at 6 hrs, 80 at 24 hrs and 85 at 72 hrs. 
  1. SEPSISPAM Study (Higher MAP vs Lower MAP target in septic shock):  Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. N Engl J Med 2014; 370:1583-1593 

Key pointers:

  1. New onset A.fib is significantly higher in high MAP group.
  2. In patients with chronic hypertension, the doubling of creatinine as well as need for RRT in first week is significantly lower in high MAP group.  
Note: In other studies as well, the benefit is lost once the MAP is above 65.  
In a study, the perfused vessel density increased when MAP’s are raised from 65 to 75 and then to 85. This indicates that by increasing MAP from 65 to 85, there may be improvement is microcirculation. Crit Care. 2011;15(5):R222  
In another study, there was no significant benefit in raising the MAP from 65 to 85 in patients who had low basal perfused capillary density. Crit care 2009, 13 R:92 
Note: Higher MAP’s may be indicated in patients with chronic hypertension, low basal perfused capillary density and in patients with elevated abdominal pressure.  
  1. CORTICUS Study (Steroids in Septic shock): Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. N Engl J Med 2008; 358:111-124 
  1. No difference in 28-day mortality.(30-35%)  
  2. Statistically significant reduction in the time to reversal of shock favoring the hydrocortisone group, 3.3 days in the hydrocortisone group vs. 5.8 days in the placebo group. (Please note that the proportion of patients who achieved reversal of shock with or without steroids remains the same at 80% vs. 75%. However, patients in whom shock was reversed, the time it took was significantly less in steroid group. Steroids just decreases the shock reversal time, if patient respond at all.) 
  3. Non-significant increase in rate of superinfections in hydrocortisone vs. placebo group 33% vs. 26%. Also, there was a minor increase in hyperglycemia and hypernatremia in hydrocortisone group. (Other studies that used steroids didn’t show any increased risk of infections). 
Key pointers: 
There was a clear benefit in mortality rates with steroids in Annane study (JAMA 2002). However, he used both hydrocortisone and fludrocortisone. Annane study was allowed only within 8 hours after fulfilling entry criteria, as compared with a 72-hour window in our study.  In the results graph, the 28 day mortality benefit curve was significantly better already by 72 hrs and it just continued for 28 days. (? Mortality benefit for steroids may only be present in 1st 72 hrs). Maybe, giving steroids within 8 hours made the difference in mortality. Also, his patients are sicker with higher SAPS 2 scores (Mean of 60).  
At baseline, the vasopressor needs in corticus study was around 0.5mcg/kg/min of levophed and in Annane study, it was around 1mcg/kg/min. The severity of shock was lot more in annane group than in corticus group. May be, steroids are most helpful if vasopressors requirements are more than 1mcg/kg/min.  
The duration of the administration of corticosteroids may be pertinent, with the possibility that any gain that was achieved by an earlier reversal of shock was counterbalanced by later complications. In the Annane study, corticosteroid treatment was stopped abruptly after 7 days, whereas in our study, therapy was tapered from day 6 to day 12.  
  1. Steroids in Septic Shock (Annane Study ): Low dose hydrocortisone and fludrocortisone therapy significantly reduced 28 day mortality in relative adrenal insufficiency (non-responders to Cosyntropin), 53% VS 63%. No significant difference in all patients combined. Also, time for vasopressor withdrawal was better with steroids, 7 days in steroid vs. 9 days with placebo.  Rate of adverse effects were similar including infections and GI bleed.   JAMA. 2002;288(7):862-871
Key pointers: 
On subgroup analysis, the 28 day mortality was higher with steroids in responders, 61 in steroids vs. 53 in placebo.   Average cortisol level before Cosyntropin test in responders is 30 and in non-responders is 18. After Cosyntropin, the cortisol level remained around 20 in non-responders but increased to 55 in responders.  Cortisol level in all patients combined before test is 20 and after test is 28. Is giving steroids to a patient (responders) who already had a cortisol>55 the reason for increased mortality?  
The high mortality rates in this study could possibly because of delayed administration of antibiotics (5-6 hrs in non-responders vs. 9 hrs in responders). 
In another study, single dose of 50mg hydrocortisone greatly improved vasopressor dose-response relationship in septic shock with relative adrenal insufficiency.  
This study found that patients with septic shock and relative adrenal deficiency, who were treated with low dose steroids, had a significantly improved mortality. This is in contrast to the CORTICUS study which found no improvement in mortality. However, CORTICUS was only powered at 35% to detect a 20% relative reduction of death (ref: editorial).  ADRENAL study is ongoing.  
Conclusions : 
In Cosyntropin non responders (Relative adrenal insufficiency), Low dose hydrocortisone and fludrocortisone reduced the risk of death in patients with septic shock (especially if basal cortisol level is less than 20) without increasing adverse events like infections. The median time for vasopressor withdrawal was 7 days in steroid group vs. 10 days in placebo group. Also, within first 28 days, more patients were off vasopressors in steroid group than in placebo group. 
In Cosyntropin responders, there was no significant difference between the groups.  The key question is did steroids improve mortality in non responders or did steroids worsen mortality in responders? 
Corticus vs. Annane
My take home message: Give steroids if cortisol is less than 20 and give them earlier, preferably within 8 hours and stop it within 72 hrs, at the most within a week.  Also, use steroids if vasopressor requirements are more than 1mcg/kg/min in the first 6 hours. When you are adding second vasopressor, its time to think of adding steroids. Other studies also showed that in septic shock, low doses of hydrocortisone can restore vascular responsiveness to catecholamines. Consider stopping steroids when patient no longer needs vasopressors. 
  1. ALBIOS Study (Albumin vs. Crystalloids): The use of 20% albumin in adults with severe sepsis or septic shock will improve hemodynamic indices, but will not reduce mortality ,length of stay, mechanical ventilation, 90 day mortality or other secondary organ dysfunction. Its use is safe but not recommended for routine fluid resuscitation. Targeting a serum albumin of 3g/dl or more does not appear to have a survival advantage. N Engl J Med 2014; 370:1412-1421 
Key pointers: 
20% albumin was administered on a daily basis, to maintain serum albumin equal or greater than 3 g/dL.  This study is little different from SAFE study in that the amount of albumin used in this study is much lower and the goal was to increase albumin level rather than improve hemodynamics as in SAFE study. However, in a post hoc analysis of ALBIOS study, there was some mortality benefit in the sub group of patients with septic shock (43% vs. 50%).  
  1. SAFE Study (Albumin vs. Crystalloids in ICU): In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days. N Engl J Med 2004; 350:2247-2256 
  • Causes of hyperlactatemia in sepsis include endogenous catecholamine release, hypoxia and hypotension, beta agonist mediated, inhibition of pyruvate dehydrogenase and thereby decreased lactate clearance in liver. 
  •  As per Dr.Paul Marik , lactate is produced from beta agonist effects of catecholamines released from stress but not from anaerobic metabolism. In sick states, the body changes its energy substrate to lactate from glucose. Hence, more lactic acid is produced. It just indicates how sick you are. By trying to clear lactate with increased perfusion, there is no benefit and we are depriving the body of lactate. Also, supra physiological doses of oxygen delivery is harmful. In a study, infusion of sodium lactate improved cardiac function. Maybe, this will convince to use RL instead of NS. 
  • SSC guidelines suggested against the use of sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15.
  • Mean arterial pressure vs Systolic blood pressure: Quite often we see clinicians targetting a systolic blood pressure of 90 or whatever makes them comfortable. However, body doesn't just perfuse during systole only. Hence, MAP rather than systolic blood pressure is the preferred metric in the ICU to guide therapy. Crit Care Med. 2013 Jan; 41(1): 34–40

Leave a Comment